Ethyl 2-(1,2,3,4-tetrahydro­spiro­[carba­zole-3,2′-[1,3]dioxolan]-9-yl)acetate

Löffler, P.M.G.; Ulven, T.; Bond, A.D.

doi:10.1107/S160053680900748X

organic compounds

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ISSN: 2056-9890

Volume 65| Part 4| April 2009| Page o685

doi:10.1107/S160053680900748X

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Ethyl 2-(1,2,3,4-tetrahydrospiro[carbazole-3,2′-[1,3]dioxolan]-9-yl)acetate

Philipp M. G. Löffler,^a Trond Ulven ^a and Andrew D. Bond ^a ^*

^aUniversity of Southern Denmark, Department of Physics and Chemistry, Campusvej 55, 5230 Odense M, Denmark
^*Correspondence e-mail: adb@chem.sdu.dk

(Received 19 February 2009; accepted 1 March 2009; online 6 March 2009)

In the title compound, C₁₈H₂₁NO₄, the hydrogenated six-membered ring of the carbazole unit adopts a half-chair conformation. The dioxolane ring and ethylacetate substituent point to opposite sides of the carbazole plane. The ethylacetate substituent adopts an essentially fully extended conformation, and its mean plane forms a dihedral angle of 83.8 (1)° with respect to the carbazole mean plane. The molecules are arranged into stacks in which the carbazole planes form a dihedral angle of 4.4 (1)° and have an approximate interplanar separation of 3.6 Å.

Related literature

For background literature and synthesis details, see: Ulven & Kostenis (2005 , 2006 ). For a related structure, see: Bjerrum et al. (2009 ).

Experimental

Crystal data

C₁₈H₂₁NO₄
M_r = 315.36
Monoclinic, P 2₁ /c
a = 10.5533 (4) Å
b = 17.3773 (6) Å
c = 8.9637 (3) Å
β = 105.629 (1)°
V = 1583.05 (10) Å³
Z = 4
Mo Kα radiation
μ = 0.09 mm⁻¹
T = 180 K
0.50 × 0.50 × 0.10 mm

Data collection

Bruker-Nonius X8 APEXII CCD diffractometer
Absorption correction: multi-scan (SADABS; Sheldrick, 2003 ) T_min = 0.847, T_max = 0.991
25055 measured reflections
3851 independent reflections
3174 reflections with I > 2σ(I)
R_int = 0.025

Refinement

R[F² > 2σ(F²)] = 0.040
wR(F²) = 0.112
S = 1.04
3851 reflections
208 parameters
H-atom parameters constrained
Δρ_max = 0.28 e Å⁻³
Δρ_min = −0.25 e Å⁻³

Data collection: APEX2 (Bruker, 2004 ); cell refinement: SAINT (Bruker, 2003 ); data reduction: SAINT; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008 ); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: SHELXTL (Sheldrick, 2008); software used to prepare material for publication: SHELXTL.

Supporting information

Crystal structure: contains datablocks global, I. DOI: 10.1107/S160053680900748X/xu2485sup1.cif

Structure factors: contains datablock I. DOI: 10.1107/S160053680900748X/xu2485Isup2.hkl

checkCIF report

Comment top

The title compound is useful as an intermediate in the synthesis of antagonists of the prostaglandin D₂ receptor CRTH2 (DP₂) (Ulven & Kostenis, 2006).

Related literature top

For background literature and synthesis details, see: Ulven & Kostenis (2006); Ulven & Kostenis (2005). For a related structure, see: Bjerrum et al. (2009).

Experimental top

The compound was synthesized as described in Ulven & Kostenis (2005).

Computing details top

Data collection: APEX2 (Bruker, 2004); cell refinement: SAINT (Bruker, 2003); data reduction: SAINT (Bruker, 2003); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: SHELXTL (Sheldrick, 2008); software used to prepare material for publication: SHELXTL (Sheldrick, 2008).

Figures top

	Fig. 1. Molecular structure of the title compound with displacement ellipsoids shown at 50% probability for non-H atoms.
	Fig. 2. Packing diagram viewed along the c axis, showing stacked carbazole units. H atoms are omitted.

Ethyl 2-(1,2,3,4-tetrahydrospiro[carbazole-3,2'-[1,3]dioxolan]-9-yl)acetate top

Crystal data top

C₁₈H₂₁NO₄	F(000) = 672
M_r = 315.36	D_x = 1.323 Mg m⁻³
Monoclinic, P2₁/c	Mo Kα radiation, λ = 0.71073 Å
Hall symbol: -P 2ybc	Cell parameters from 7203 reflections
a = 10.5533 (4) Å	θ = 2.0–28.2°
b = 17.3773 (6) Å	µ = 0.09 mm⁻¹
c = 8.9637 (3) Å	T = 180 K
β = 105.629 (1)°	Plate, brown
V = 1583.05 (10) Å³	0.50 × 0.50 × 0.10 mm
Z = 4

Data collection top

Bruker-Nonius X8 APEXII CCD diffractometer	3851 independent reflections
Radiation source: fine-focus sealed tube	3174 reflections with I > 2σ(I)
Graphite monochromator	R_int = 0.025
thin–slice ω and ϕ scans	θ_max = 28.3°, θ_min = 3.5°
Absorption correction: multi-scan (SADABS; Sheldrick, 2003)	h = −13→13
T_min = 0.847, T_max = 0.991	k = −23→21
25055 measured reflections	l = −11→11

Refinement top

Refinement on F²	Primary atom site location: structure-invariant direct methods
Least-squares matrix: full	Secondary atom site location: difference Fourier map
R[F² > 2σ(F²)] = 0.040	Hydrogen site location: inferred from neighbouring sites
wR(F²) = 0.112	H-atom parameters constrained
S = 1.04	w = 1/[σ²(F_o²) + (0.0568P)² + 0.4296P] where P = (F_o² + 2F_c²)/3
3851 reflections	(Δ/σ)_max < 0.001
208 parameters	Δρ_max = 0.28 e Å⁻³
0 restraints	Δρ_min = −0.25 e Å⁻³

Crystal data top

C₁₈H₂₁NO₄	V = 1583.05 (10) Å³
M_r = 315.36	Z = 4
Monoclinic, P2₁/c	Mo Kα radiation
a = 10.5533 (4) Å	µ = 0.09 mm⁻¹
b = 17.3773 (6) Å	T = 180 K
c = 8.9637 (3) Å	0.50 × 0.50 × 0.10 mm
β = 105.629 (1)°

Data collection top

Bruker-Nonius X8 APEXII CCD diffractometer	3851 independent reflections
Absorption correction: multi-scan (SADABS; Sheldrick, 2003)	3174 reflections with I > 2σ(I)
T_min = 0.847, T_max = 0.991	R_int = 0.025
25055 measured reflections

Refinement top

R[F² > 2σ(F²)] = 0.040	0 restraints
wR(F²) = 0.112	H-atom parameters constrained
S = 1.04	Δρ_max = 0.28 e Å⁻³
3851 reflections	Δρ_min = −0.25 e Å⁻³
208 parameters

Special details top

Geometry. All e.s.d.'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.'s are taken into account individually in the estimation of e.s.d.'s in distances, angles and torsion angles; correlations between e.s.d.'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.'s is used for estimating e.s.d.'s involving l.s. planes.

Refinement. Refinement of F² against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F², conventional R-factors R are based on F, with F set to zero for negative F². The threshold expression of F² > σ(F²) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F² are statistically about twice as large as those based on F, and R- factors based on ALL data will be even larger.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å²) top

	x	y	z	U_iso*/U_eq
O1	1.21234 (9)	0.15818 (7)	1.12008 (10)	0.0460 (3)
O2	1.17774 (8)	0.16828 (5)	0.85930 (9)	0.0310 (2)
O3	0.54620 (9)	0.18009 (6)	0.72948 (11)	0.0431 (2)
O4	0.48419 (8)	0.12028 (5)	0.50032 (10)	0.0319 (2)
N1	0.76683 (9)	0.24098 (6)	0.66065 (11)	0.0269 (2)
C1	0.76918 (11)	0.32014 (7)	0.67550 (13)	0.0271 (2)
C2	0.68683 (13)	0.37599 (8)	0.58858 (16)	0.0375 (3)
H2A	0.6137	0.3624	0.5048	0.045*
C3	0.71574 (15)	0.45191 (8)	0.62915 (18)	0.0459 (3)
H3A	0.6611	0.4912	0.5719	0.055*
C4	0.82262 (15)	0.47257 (8)	0.75148 (18)	0.0428 (3)
H4A	0.8399	0.5254	0.7756	0.051*
C5	0.90393 (13)	0.41716 (7)	0.83833 (15)	0.0339 (3)
H5A	0.9766	0.4316	0.9219	0.041*
C6	0.87768 (11)	0.33951 (6)	0.80135 (13)	0.0263 (2)
C7	0.93961 (10)	0.26886 (6)	0.86264 (13)	0.0256 (2)
C8	1.06186 (12)	0.25587 (8)	0.99027 (14)	0.0324 (3)
H8A	1.0427	0.2630	1.0916	0.039*
H8B	1.1296	0.2940	0.9825	0.039*
C9	1.11382 (11)	0.17469 (7)	0.98003 (13)	0.0305 (3)
C10	1.00563 (12)	0.11489 (7)	0.95185 (14)	0.0334 (3)
H10A	0.9625	0.1170	1.0371	0.040*
H10B	1.0448	0.0631	0.9526	0.040*
C11	0.90183 (12)	0.12724 (7)	0.79701 (14)	0.0311 (3)
H11A	0.9359	0.1086	0.7109	0.037*
H11B	0.8213	0.0977	0.7958	0.037*
C12	0.86989 (10)	0.21090 (6)	0.77637 (13)	0.0255 (2)
C13	1.33628 (14)	0.16069 (11)	1.09153 (17)	0.0486 (4)
H13A	1.3774	0.1090	1.1043	0.058*
H13B	1.3950	0.1968	1.1636	0.058*
C14	1.31189 (12)	0.18790 (9)	0.92705 (15)	0.0398 (3)
H14A	1.3257	0.2441	0.9228	0.048*
H14B	1.3704	0.1612	0.8740	0.048*
C15	0.67326 (11)	0.19717 (7)	0.54503 (13)	0.0290 (2)
H15A	0.7192	0.1537	0.5107	0.035*
H15B	0.6361	0.2304	0.4540	0.035*
C16	0.56219 (11)	0.16596 (6)	0.60498 (13)	0.0264 (2)
C17	0.37837 (12)	0.08256 (8)	0.54942 (15)	0.0373 (3)
H17A	0.3230	0.1215	0.5826	0.045*
H17B	0.4156	0.0477	0.6377	0.045*
C18	0.29786 (13)	0.03789 (8)	0.41509 (16)	0.0407 (3)
H18A	0.2259	0.0120	0.4450	0.061*
H18B	0.3534	−0.0006	0.3835	0.061*
H18C	0.2613	0.0729	0.3285	0.061*

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
O1	0.0307 (5)	0.0794 (7)	0.0284 (5)	0.0149 (5)	0.0090 (4)	0.0144 (4)
O2	0.0270 (4)	0.0428 (5)	0.0261 (4)	0.0009 (3)	0.0119 (3)	0.0002 (3)
O3	0.0339 (5)	0.0658 (6)	0.0338 (5)	−0.0159 (4)	0.0163 (4)	−0.0132 (4)
O4	0.0255 (4)	0.0388 (5)	0.0317 (4)	−0.0088 (3)	0.0081 (3)	−0.0039 (3)
N1	0.0220 (5)	0.0306 (5)	0.0275 (5)	−0.0043 (4)	0.0057 (4)	−0.0010 (4)
C1	0.0241 (5)	0.0308 (6)	0.0295 (5)	−0.0023 (4)	0.0126 (4)	0.0011 (4)
C2	0.0323 (6)	0.0439 (7)	0.0371 (6)	0.0055 (5)	0.0106 (5)	0.0077 (5)
C3	0.0507 (8)	0.0371 (7)	0.0540 (8)	0.0124 (6)	0.0211 (7)	0.0119 (6)
C4	0.0532 (8)	0.0284 (6)	0.0553 (8)	0.0005 (6)	0.0294 (7)	−0.0007 (6)
C5	0.0356 (6)	0.0329 (6)	0.0385 (6)	−0.0058 (5)	0.0193 (5)	−0.0072 (5)
C6	0.0247 (5)	0.0302 (6)	0.0280 (5)	−0.0022 (4)	0.0138 (4)	−0.0017 (4)
C7	0.0227 (5)	0.0307 (6)	0.0256 (5)	−0.0016 (4)	0.0100 (4)	−0.0027 (4)
C8	0.0264 (6)	0.0425 (7)	0.0270 (6)	0.0004 (5)	0.0051 (4)	−0.0068 (5)
C9	0.0264 (6)	0.0444 (7)	0.0221 (5)	0.0054 (5)	0.0092 (4)	0.0046 (5)
C10	0.0331 (6)	0.0362 (6)	0.0350 (6)	0.0046 (5)	0.0160 (5)	0.0083 (5)
C11	0.0299 (6)	0.0284 (6)	0.0361 (6)	−0.0026 (4)	0.0109 (5)	−0.0010 (5)
C12	0.0216 (5)	0.0300 (6)	0.0263 (5)	−0.0019 (4)	0.0088 (4)	−0.0005 (4)
C13	0.0301 (7)	0.0766 (11)	0.0369 (7)	−0.0055 (7)	0.0054 (5)	−0.0011 (7)
C14	0.0288 (6)	0.0552 (8)	0.0383 (7)	−0.0054 (6)	0.0142 (5)	−0.0041 (6)
C15	0.0241 (5)	0.0381 (6)	0.0252 (5)	−0.0066 (5)	0.0073 (4)	−0.0031 (5)
C16	0.0204 (5)	0.0315 (6)	0.0265 (5)	−0.0005 (4)	0.0050 (4)	0.0002 (4)
C17	0.0277 (6)	0.0442 (7)	0.0404 (7)	−0.0096 (5)	0.0099 (5)	0.0018 (6)
C18	0.0340 (7)	0.0403 (7)	0.0445 (7)	−0.0114 (5)	0.0049 (5)	0.0023 (6)

Geometric parameters (Å, º) top

O1—C13	1.3995 (17)	C8—H8A	0.990
O1—C9	1.4268 (14)	C8—H8B	0.990
O2—C14	1.4233 (15)	C9—C10	1.5140 (18)
O2—C9	1.4254 (13)	C10—C11	1.5340 (17)
O3—C16	1.1982 (14)	C10—H10A	0.990
O4—C16	1.3311 (14)	C10—H10B	0.990
O4—C17	1.4613 (14)	C11—C12	1.4926 (16)
N1—C1	1.3817 (15)	C11—H11A	0.990
N1—C12	1.3872 (14)	C11—H11B	0.990
N1—C15	1.4412 (14)	C13—C14	1.503 (2)
C1—C2	1.3926 (17)	C13—H13A	0.990
C1—C6	1.4146 (16)	C13—H13B	0.990
C2—C3	1.381 (2)	C14—H14A	0.990
C2—H2A	0.950	C14—H14B	0.990
C3—C4	1.392 (2)	C15—C16	1.5154 (15)
C3—H3A	0.950	C15—H15A	0.990
C4—C5	1.382 (2)	C15—H15B	0.990
C4—H4A	0.950	C17—C18	1.4910 (18)
C5—C6	1.3993 (16)	C17—H17A	0.990
C5—H5A	0.950	C17—H17B	0.990
C6—C7	1.4293 (16)	C18—H18A	0.980
C7—C12	1.3591 (16)	C18—H18B	0.980
C7—C8	1.4929 (15)	C18—H18C	0.980
C8—C9	1.5252 (18)

C13—O1—C9	109.16 (9)	H10A—C10—H10B	107.9
C14—O2—C9	106.09 (9)	C12—C11—C10	109.32 (10)
C16—O4—C17	115.65 (9)	C12—C11—H11A	109.8
C1—N1—C12	108.24 (9)	C10—C11—H11A	109.8
C1—N1—C15	125.89 (10)	C12—C11—H11B	109.8
C12—N1—C15	125.87 (10)	C10—C11—H11B	109.8
N1—C1—C2	130.37 (11)	H11A—C11—H11B	108.3
N1—C1—C6	107.66 (10)	C7—C12—N1	109.97 (10)
C2—C1—C6	121.97 (11)	C7—C12—C11	125.57 (10)
C3—C2—C1	117.28 (13)	N1—C12—C11	124.41 (10)
C3—C2—H2A	121.4	O1—C13—C14	105.53 (11)
C1—C2—H2A	121.4	O1—C13—H13A	110.6
C2—C3—C4	121.92 (13)	C14—C13—H13A	110.6
C2—C3—H3A	119.0	O1—C13—H13B	110.6
C4—C3—H3A	119.0	C14—C13—H13B	110.6
C5—C4—C3	120.83 (13)	H13A—C13—H13B	108.8
C5—C4—H4A	119.6	O2—C14—C13	103.35 (10)
C3—C4—H4A	119.6	O2—C14—H14A	111.1
C4—C5—C6	119.03 (12)	C13—C14—H14A	111.1
C4—C5—H5A	120.5	O2—C14—H14B	111.1
C6—C5—H5A	120.5	C13—C14—H14B	111.1
C5—C6—C1	118.98 (11)	H14A—C14—H14B	109.1
C5—C6—C7	134.14 (11)	N1—C15—C16	112.31 (9)
C1—C6—C7	106.87 (10)	N1—C15—H15A	109.1
C12—C7—C6	107.24 (10)	C16—C15—H15A	109.1
C12—C7—C8	123.20 (11)	N1—C15—H15B	109.1
C6—C7—C8	129.47 (10)	C16—C15—H15B	109.1
C7—C8—C9	110.13 (10)	H15A—C15—H15B	107.9
C7—C8—H8A	109.6	O3—C16—O4	124.27 (10)
C9—C8—H8A	109.6	O3—C16—C15	124.99 (10)
C7—C8—H8B	109.6	O4—C16—C15	110.74 (9)
C9—C8—H8B	109.6	O4—C17—C18	107.80 (10)
H8A—C8—H8B	108.1	O4—C17—H17A	110.1
O2—C9—O1	105.70 (9)	C18—C17—H17A	110.1
O2—C9—C10	108.03 (10)	O4—C17—H17B	110.1
O1—C9—C10	110.29 (10)	C18—C17—H17B	110.1
O2—C9—C8	111.67 (10)	H17A—C17—H17B	108.5
O1—C9—C8	108.76 (10)	C17—C18—H18A	109.5
C10—C9—C8	112.19 (10)	C17—C18—H18B	109.5
C9—C10—C11	112.18 (10)	H18A—C18—H18B	109.5
C9—C10—H10A	109.2	C17—C18—H18C	109.5
C11—C10—H10A	109.2	H18A—C18—H18C	109.5
C9—C10—H10B	109.2	H18B—C18—H18C	109.5
C11—C10—H10B	109.2

C12—N1—C1—C2	−179.74 (11)	C7—C8—C9—O2	76.13 (12)
C15—N1—C1—C2	0.15 (19)	C7—C8—C9—O1	−167.60 (9)
C12—N1—C1—C6	1.15 (12)	C7—C8—C9—C10	−45.32 (13)
C15—N1—C1—C6	−178.96 (9)	O2—C9—C10—C11	−61.20 (12)
N1—C1—C2—C3	−178.46 (12)	O1—C9—C10—C11	−176.27 (9)
C6—C1—C2—C3	0.54 (18)	C8—C9—C10—C11	62.32 (13)
C1—C2—C3—C4	0.1 (2)	C9—C10—C11—C12	−43.12 (13)
C2—C3—C4—C5	−0.5 (2)	C6—C7—C12—N1	0.87 (12)
C3—C4—C5—C6	0.20 (19)	C8—C7—C12—N1	−176.05 (9)
C4—C5—C6—C1	0.41 (16)	C6—C7—C12—C11	178.28 (10)
C4—C5—C6—C7	179.11 (12)	C8—C7—C12—C11	1.36 (17)
N1—C1—C6—C5	178.40 (10)	C1—N1—C12—C7	−1.28 (12)
C2—C1—C6—C5	−0.80 (16)	C15—N1—C12—C7	178.83 (10)
N1—C1—C6—C7	−0.62 (11)	C1—N1—C12—C11	−178.72 (10)
C2—C1—C6—C7	−179.82 (10)	C15—N1—C12—C11	1.39 (16)
C5—C6—C7—C12	−178.95 (12)	C10—C11—C12—C7	12.73 (15)
C1—C6—C7—C12	−0.15 (12)	C10—C11—C12—N1	−170.22 (10)
C5—C6—C7—C8	−2.3 (2)	C9—O1—C13—C14	5.60 (16)
C1—C6—C7—C8	176.51 (11)	C9—O2—C14—C13	31.96 (14)
C12—C7—C8—C9	14.73 (15)	O1—C13—C14—O2	−23.07 (16)
C6—C7—C8—C9	−161.45 (11)	C1—N1—C15—C16	−97.30 (13)
C14—O2—C9—O1	−29.21 (13)	C12—N1—C15—C16	82.58 (13)
C14—O2—C9—C10	−147.26 (10)	C17—O4—C16—O3	−3.87 (17)
C14—O2—C9—C8	88.91 (12)	C17—O4—C16—C15	176.02 (10)
C13—O1—C9—O2	14.11 (14)	N1—C15—C16—O3	5.41 (17)
C13—O1—C9—C10	130.64 (12)	N1—C15—C16—O4	−174.47 (9)
C13—O1—C9—C8	−105.93 (13)	C16—O4—C17—C18	176.84 (10)

Experimental details

Crystal data
Chemical formula	C₁₈H₂₁NO₄
M_r	315.36
Crystal system, space group	Monoclinic, P2₁/c
Temperature (K)	180
a, b, c (Å)	10.5533 (4), 17.3773 (6), 8.9637 (3)
β (°)	105.629 (1)
V (Å³)	1583.05 (10)
Z	4
Radiation type	Mo Kα
µ (mm⁻¹)	0.09
Crystal size (mm)	0.50 × 0.50 × 0.10

Data collection
Diffractometer	Bruker-Nonius X8 APEXII CCD diffractometer
Absorption correction	Multi-scan (SADABS; Sheldrick, 2003)
T_min, T_max	0.847, 0.991
No. of measured, independent and observed [I > 2σ(I)] reflections	25055, 3851, 3174
R_int	0.025
(sin θ/λ)_max (Å⁻¹)	0.667

Refinement
R[F² > 2σ(F²)], wR(F²), S	0.040, 0.112, 1.04
No. of reflections	3851
No. of parameters	208
H-atom treatment	H-atom parameters constrained
Δρ_max, Δρ_min (e Å⁻³)	0.28, −0.25

Computer programs: APEX2 (Bruker, 2004), SAINT (Bruker, 2003), SHELXS97 (Sheldrick, 2008), SHELXL97 (Sheldrick, 2008), SHELXTL (Sheldrick, 2008).

Acknowledgements

We are grateful to the Danish Natural Sciences Research Council and the Carlsberg Foundation for provision of the X-ray equipment.

References

Bjerrum, J. V., Ulven, T. & Bond, A. D. (2009). Acta Cryst. E65, o579. Web of Science CSD CrossRef IUCr Journals Google Scholar
Bruker (2003). SAINT. Bruker AXS Inc., Madison, Wisconsin, USA. Google Scholar
Bruker (2004). APEX2. Bruker AXS Inc., Madison, Wisconsin, USA. Google Scholar
Sheldrick, G. M. (2003). SADABS. Bruker AXS Inc., Madison, Wisconsin, USA. Google Scholar
Sheldrick, G. M. (2008). Acta Cryst. A64, 112–122. Web of Science CrossRef CAS IUCr Journals Google Scholar
Ulven, T. & Kostenis, E. (2005). J. Med. Chem. 48, 897–900. Web of Science CrossRef PubMed CAS Google Scholar
Ulven, T. & Kostenis, E. (2006). Curr. Top. Med. Chem. 6, 1427–1444. Web of Science CrossRef PubMed CAS Google Scholar